Anesthesia and the Developing Brain: A Review of Sevoflurane-induced Neurotoxicity in Pediatric Populations

Apai, Carol; Shah, Rohan; Tran, Khoa; Shah, Shridevi Pandya

doi:10.1016/j.clinthera.2021.01.024

Cited by 22 publications

(14 citation statements)

References 48 publications

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“… 2020 ; Apai et al. 2021 ). Besides, Ech has been proved to reduce LDH level and attenuate apoptosis in the cardiomyocyte of myocardial ischemic/reperfusion mice (Niu et al.…”

Section: Discussionmentioning

confidence: 99%

Echinatin mitigates sevoflurane-induced hippocampal neurotoxicity and cognitive deficits through mitigation of iron overload and oxidative stress

You

Tang

et al. 2022

Pharmaceutical Biology

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Context Sevoflurane (Sev) is a commonly used surgical anaesthetic; it has neurotoxic effects on the brain. Echinatin (Ech) is reported to have anti-inflammatory and antioxidant activity. Objective This research confirms the effect of Ech on Sev-induced neurotoxicity and cognitive deficits. Materials and methods Primary rat hippocampal neurons were treated with 4.1% Sev for 6 h in the presence of Ech (5, 10, and 20 μM) or vehicle, followed by a further 42 h of culture. Male Sprague-Dawley aged rats were divided into 6 groups ( n = 6): control, Sev, Sev + Ech (20 mg/kg;), Sev + Ech (40 mg/kg), and Sev + Ech (80 mg/kg). Rats were intraperitoneally injected with Ech or vehicle 1 h before Sev exposure (2% Sev for 5 h). Results We found that Ech (5, 10, and 20 μM) elevated cell viability (1.29-, 1.51-, 1.68-fold) but mitigated apoptosis (23.87% vs. 16.48%, 12.72%, 9.02%), oxidative stress, and ferroptosis in hippocampal neurons with Sev treatment. Ech activated the Nrf2 expression in Sev-induced in vitro and in vivo models of anaesthetic neurotoxicity. Ech also weakened neurotoxicity in hippocampal neurons with Sev treatment by increasing Nrf2 expression level. Moreover, Ech alleviated hippocampus neurons apoptosis (19.38% vs. 16.05%, 11.71%, 8.88%), oxidative stress, and ferroptosis in rats with Sev treatment. Ech improved Sev-induced cognitive deficits in rats. Conclusions Ech alleviates Sev-induced neurotoxicity and cognitive deficits by mitigation of ferroptosis and oxidative stress. Ech may be developed as a new promising therapeutic drug for treatment of cerebral nerve injury caused by surgical anaesthesia.

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“… 2020 ; Apai et al. 2021 ). Besides, Ech has been proved to reduce LDH level and attenuate apoptosis in the cardiomyocyte of myocardial ischemic/reperfusion mice (Niu et al.…”

Section: Discussionmentioning

confidence: 99%

Echinatin mitigates sevoflurane-induced hippocampal neurotoxicity and cognitive deficits through mitigation of iron overload and oxidative stress

You

Tang

et al. 2022

Pharmaceutical Biology

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“…Our findings that intravenous Tempol, a scavenger of free-radicals/superoxide anion, attenuates OIRD elicited by morphine or fentanyl ( Baby S. et al, 2021 ; Baby S. M. et al, 2021 ) points to the importance of redox mechanisms in opioid actions and possibly the ability of thiolesters to overcome OIRD. The effectiveness of L-CYSme to overcome the adverse effects of morphine in unanesthetized rats and in sevoflurane-anesthetized rats, the most clinically-relevant gaseous anesthetic ( Aoki et al, 2021 ; Apai et al, 2021 ; Liang et al, 2021 ), supports the necessity of further studies with L-CYSme in pre-clinical models of OIRD, such as dogs ( Walker et al, 1967 ; Lemmens et al, 2008 ) or goats ( Hubbard et al, 1992 ; Heard et al, 1996 ) that bridge potential clinical trials studies in humans.…”

Section: Discussionmentioning

confidence: 99%

“…This finding that L-cysteine was inactive suggests that the effects of L-CYSee were due to entry of the L-thiolester into cells that initiate intracellular signaling events that overcome OIRD, but also obstruct the upper airway (e.g., collapse of the larynx, closure of the vocal folds, flaccid tongue that retracts and occludes the airway). The adverse effects of a combination of L-CYSee and morphine on the upper airway may involve the pharmacological actions of isoflurane since these effects of L-CYSee were not seen in sevoflurane-anesthetized rat ( Bates et al, 1991 ), which is the dominant clinical gaseous anesthetic ( Aoki et al, 2021 ; Apai et al, 2021 ; Liang et al, 2021 ). Here we extend our knowledge of L-thiolesters by describing the actions of L-CYSme on the effects of morphine in unanesthetized, unrestrained male Sprague Dawley rats.…”

Section: Introductionmentioning

confidence: 99%

L-cysteine methyl ester overcomes the deleterious effects of morphine on ventilatory parameters and arterial blood-gas chemistry in unanesthetized rats

Getsy

Baby²,

May³

et al. 2022

Front. Pharmacol.

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We are developing a series of thiolesters that produce an immediate and sustained reversal of the deleterious effects of opioids, such as morphine and fentanyl, on ventilation without diminishing the antinociceptive effects of these opioids. We report here the effects of systemic injections of L-cysteine methyl ester (L-CYSme) on morphine-induced changes in ventilatory parameters, arterial-blood gas (ABG) chemistry (pH, pCO2, pO2, sO2), Alveolar-arterial (A-a) gradient (i.e., the index of alveolar gas-exchange within the lungs), and antinociception in unanesthetized Sprague Dawley rats. The administration of morphine (10 mg/kg, IV) produced a series of deleterious effects on ventilatory parameters, including sustained decreases in tidal volume, minute ventilation, inspiratory drive and peak inspiratory flow that were accompanied by a sustained increase in end inspiratory pause. A single injection of L-CYSme (500 μmol/kg, IV) produced a rapid and long-lasting reversal of the deleterious effects of morphine on ventilatory parameters, and a second injection of L-CYSme (500 μmol/kg, IV) elicited pronounced increases in ventilatory parameters, such as minute ventilation, to values well above pre-morphine levels. L-CYSme (250 or 500 μmol/kg, IV) also produced an immediate and sustained reversal of the deleterious effects of morphine (10 mg/kg, IV) on arterial blood pH, pCO2, pO2, sO2 and A-a gradient, whereas L-cysteine (500 μmol/kg, IV) itself was inactive. L-CYSme (500 μmol/kg, IV) did not appear to modulate the sedative effects of morphine as measured by righting reflex times, but did diminish the duration, however, not the magnitude of the antinociceptive actions of morphine (5 or 10 mg/kg, IV) as determined in tail-flick latency and hindpaw-withdrawal latency assays. These findings provide evidence that L-CYSme can powerfully overcome the deleterious effects of morphine on breathing and gas-exchange in Sprague Dawley rats while not affecting the sedative or early stage antinociceptive effects of the opioid. The mechanisms by which L-CYSme interferes with the OR-induced signaling pathways that mediate the deleterious effects of morphine on ventilatory performance, and by which L-CYSme diminishes the late stage antinociceptive action of morphine remain to be determined.

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“…It could be hypothesized that anesthesia involved sevoflurane, the most currently used anesthetics in pediatric anesthesia in France. 34 Moreover, no perioperative anesthetic complications were reported in the health records. The second limitation is that the GA-exposed children were exposed at various ages.…”

Section: Limitations and Perspectivesmentioning

confidence: 99%

Consequences of General Anesthesia in Infancy on Behavior and Brain Structure

Salaün

Chagnot

Cachia

et al. 2022

Anesthesia &Amp; Analgesia

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BACKGROUND: One in 7 children will need general anesthesia (GA) before the age of 3. Brain toxicity of anesthetics is controversial. Our objective was to clarify whether exposure of GA to the developing brain could lead to lasting behavioral and structural brain changes. METHODS: A first study was performed in mice. The behaviors (fear conditioning, Y-maze, and actimetry) and brain anatomy (high-resolution magnetic resonance imaging) of 6- to 8-week-old Swiss mice exposed or not exposed to GA from 4 to 10 days old were evaluated. A second study was a complementary analysis from the preexisting APprentissages EXécutifs et cerveau chez les enfants d’âge scolaire (APEX) cohort to assess the replicability of our data in humans. The behaviors (behavior rating inventory of executive function, emotional control, and working memory score, Backward Digit Span, and Raven 36) and brain anatomy (high-resolution magnetic resonance imaging) were compared in 102 children 9 to 10 years of age exposed or not exposed to a single GA (surgery) during infancy. RESULTS: The animal study revealed chronic exacerbated fear behavior in the adult mice (95% confidence interval [CI], 4–80; P = .03) exposed to postnatal GA; this was associated with an 11% (95% CI, 7.5–14.5) reduction of the periaqueductal gray matter (P = .046). The study in humans suggested lower emotional control (95% CI, 0.33–9.10; P = .06) and a 6.1% (95% CI, 4.3–7.8) reduction in the posterior part of the right inferior frontal gyrus (P = .019) in the children who had been exposed to a single GA procedure. CONCLUSIONS: The preclinical and clinical findings of these independent studies suggest lasting effects of early life exposure to anesthetics on later emotional control behaviors and brain structures.

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Anesthesia and the Developing Brain: A Review of Sevoflurane-induced Neurotoxicity in Pediatric Populations

Cited by 22 publications

References 48 publications

Echinatin mitigates sevoflurane-induced hippocampal neurotoxicity and cognitive deficits through mitigation of iron overload and oxidative stress

Echinatin mitigates sevoflurane-induced hippocampal neurotoxicity and cognitive deficits through mitigation of iron overload and oxidative stress

L-cysteine methyl ester overcomes the deleterious effects of morphine on ventilatory parameters and arterial blood-gas chemistry in unanesthetized rats

Consequences of General Anesthesia in Infancy on Behavior and Brain Structure

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